Skip to main content

Advertisement

SpringerLink
Log in

Characterization of Bone Marrow Progenitor Cell Uterine Engraftment and Transdifferentiation

  • Reproductive Biology: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Regeneration of uterine tissue is an important physiological process that allows for maintenance of fertility after menstruation or pregnancy. Stem cells, especially bone marrow–derived progenitors, play a crucial role in this regeneration. Here, we describe the conversion of DsRed-labeled bone marrow–derived stem cells (BMDSCs) into specific uterine cell types with both differentiated and stem cell properties in a murine model. Irradiated recipient mice underwent bone marrow transplant with DsRed-expressing BMDSCs and were analyzed for engraftment and differentiation of BMDSCs in the uterus after 2, 6, and 16 weeks. Microarray and qRT-PCR analysis of bone marrow–derived cells obtained from the uterus identified upregulation of markers indicating a contribution to the population of stromal, epithelial, endothelial, and muscle cells, followed by a late expansion of epithelial cells. Other engrafted BMDSCs in the uterus were characterized by the continued expression of specific stem cell markers such as Sca1, CD44, CD146, and CD133, indicating the some BMDSCs remain as progenitor cells. BMDSCs established in recipient mice by the 16th week were sorted by flow cytometry using DsRed and progenitor cell surface markers. In vitro cell culture studies showed that single sorted cells had clonogenic properties. These results suggest that engrafted BMDSCs in the uterus had both a stem cell component and were able to differentiate into several differentiated cell types. The pool of progenitor cells likely continues to supply differentiated uterine cells in the process of uterine repair and remodeling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

Available with Ramanaiah Mamillapalli and Hugh Taylor.

References

  1. Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell. 1997;88(3):287–98.

    Article  CAS  Google Scholar 

  2. Lin CS, et al. Recent advances in andrology-related stem cell research. Asian J Androl. 2008;10(2):171–5.

    Article  Google Scholar 

  3. Chung E. Stem-cell-based therapy in the field of urology: a review of stem cell basic science, clinical applications and future directions in the treatment of various sexual and urinary conditions. Expert Opin Biol Ther. 2015;15(11):1623–32.

    Article  Google Scholar 

  4. Kiefer JC. Primer and interviews: the dynamic stem cell niche. Dev Dyn. 2011;240(3):737–43.

    Article  Google Scholar 

  5. Lv B, et al. Biomaterial-supported MSC transplantation enhances cell-cell communication for spinal cord injury. Stem Cell Res Ther. 2021;12(1):36.

    Article  CAS  Google Scholar 

  6. Chumnanvej S, Chumnanvej S. Autologous bone-marrow mononuclear stem cell therapy in patients with stroke: a meta-analysis of comparative studies. Biomed Eng Online. 2020;19(1):74.

    Article  Google Scholar 

  7. Chen S, et al. Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. J Invasive Cardiol. 2006;18(11):552–6.

    PubMed  Google Scholar 

  8. Mazzini L, et al. Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study. Cytotherapy. 2012;14(1):56–60.

    Article  Google Scholar 

  9. Műzes G, Sipos F. Issues and opportunities of stem cell therapy in autoimmune diseases. World J Stem Cells. 2019;11(4):212–21.

    Article  Google Scholar 

  10. Venkataramana NK, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res. 2010;155(2):62–70.

    Article  CAS  Google Scholar 

  11. Ball LM, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol. 2013;163(4):501–9.

    Article  CAS  Google Scholar 

  12. McCulloch EA, Till JE. Proliferation of hemopoietic colony-forming cells transplanted into irradiated mice. Radiat Res. 1964;22:383–97.

    Article  CAS  Google Scholar 

  13. Till JE, McCulloch EA, Siminovitch L. A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proc Natl Acad Sci U S A. 1964;51(1):29–36.

    Article  CAS  Google Scholar 

  14. Sun C, et al. Neurotrophic effect of bone marrow mesenchymal stem cells for erectile dysfunction in diabetic rats. Int J Androl. 2012;35(4):601–7.

    Article  CAS  Google Scholar 

  15. Krause DS, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105(3):369–77.

    Article  CAS  Google Scholar 

  16. Gargett CE, Nguyen HP, Ye L. Endometrial regeneration and endometrial stem/progenitor cells. Rev Endocr Metab Disord. 2012;13(4):235–51.

    Article  CAS  Google Scholar 

  17. Critchley HOD, et al. Menstruation: science and society. Am J Obstet Gynecol. 2020;223(5):624–64.

    Article  Google Scholar 

  18. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1):81–5.

    Article  CAS  Google Scholar 

  19. Mints M, et al. Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient. Hum Reprod. 2008;23(1):139–43.

    Article  CAS  Google Scholar 

  20. Ikoma T, et al. Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. Am J Obstet Gynecol. 2009;201(6):608.e1-8.

    Article  Google Scholar 

  21. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. STEM CELLS. 2007;25(8):2082–6.

    Article  CAS  Google Scholar 

  22. Du H, Naqvi H, Taylor HS. Ischemia/reperfusion injury promotes and granulocyte-colony stimulating factor inhibits migration of bone marrow-derived stem cells to endometrium. Stem Cells Dev. 2012;21(18):3324–31.

    Article  CAS  Google Scholar 

  23. Morelli SS, Rameshwar P, Goldsmith LT. Experimental evidence for bone marrow as a source of nonhematopoietic endometrial stromal and epithelial compartment cells in a murine model. Biol Reprod. 2013;89(1):7.

    Article  Google Scholar 

  24. Pluchino N, Taylor HS. Endometriosis and stem cell trafficking. Reprod Sci. 2016;23(12):1616–9.

    Article  CAS  Google Scholar 

  25. Pluchino N, et al. CXCR4 or CXCR7 antagonists treat endometriosis by reducing bone marrow cell trafficking. J Cell Mol Med. 2020;24(4):2464–74.

    Article  CAS  Google Scholar 

  26. Tal R. et al. Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy. PLoS Biol, 2019. 17(9): e3000421.

  27. Moridi I, et al. CXCL12 attracts bone marrow-derived cells to uterine leiomyomas. Reprod Sci. 2020;27(9):1724–30.

    Article  CAS  Google Scholar 

  28. Chen P. et al. Endometriosis cell proliferation induced by bone marrow mesenchymal stem cells. Reprod Sci, 2020.

  29. Tal R, et al. A murine 5-fluorouracil-based submyeloablation model for the study of bone marrow-derived cell trafficking in reproduction. Endocrinology. 2016;157(10):3749–59.

    Article  CAS  Google Scholar 

  30. Sakr S, et al. Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment. Endocrinology. 2014;155(4):1489–97.

    Article  Google Scholar 

  31. Anglesio MS, et al. Cancer-associated mutations in endometriosis without cancer. N Engl J Med. 2017;376(19):1835–48.

    Article  Google Scholar 

  32. Baustian C, Hanley S, Ceredig R. Isolation, selection and culture methods to enhance clonogenicity of mouse bone marrow derived mesenchymal stromal cell precursors. Stem Cell Res Ther. 2015;6(1):151.

    Article  Google Scholar 

  33. Wolff EF, et al. Demonstration of multipotent stem cells in the adult human endometrium by in vitro chondrogenesis. Reprod Sci. 2007;14(6):524–33.

    Article  CAS  Google Scholar 

  34. Yin M. et al. CD34(+)KLF4(+) Stromal stem cells contribute to endometrial regeneration and repair. Cell Rep, 2019. 27(9): 2709–2724 e3.

  35. Sahin Ersoy G. et al. CXCL12 promotes stem cell recruitment and uterine repair after injury in Asherman’s syndrome. Molecular Therapy - Methods & Clinical Development. 4: p. 169–177.

  36. Alawadhi F. et al. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman's syndrome. PLoS ONE, 2014. 9(5): e96662.

  37. Taylor HS, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377(1):28–40.

    Article  CAS  Google Scholar 

  38. Guo SW. Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology. Hum Reprod Update. 2020;26(3):423–49.

    Article  Google Scholar 

  39. Koppolu A. et al. Epithelial cells of deep infiltrating endometriosis harbor mutations in cancer driver genes. Cells 2021. 10(4).

  40. Suda K, et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 2018;24(7):1777–89.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by NIH U54 HD052668 and R01 HD076422.

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA

    Ramanaiah Mamillapalli, Levent Mutlu & Hugh S. Taylor

Authors
  1. Ramanaiah Mamillapalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Levent Mutlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hugh S. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramanaiah Mamillapalli.

Ethics declarations

Ethics Approval

Ethics followed approved by the Yale University.

Consent for Publication

All authors gave consent to publish the data.

Conflict of Interest

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mamillapalli, R., Mutlu, L. & Taylor, H.S. Characterization of Bone Marrow Progenitor Cell Uterine Engraftment and Transdifferentiation. Reprod. Sci. 29, 2382–2390 (2022). https://doi.org/10.1007/s43032-021-00738-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-021-00738-5

Keywords

Search

Navigation